Previous work on this project has demonstrated that reward-based decision making requires direct functional interaction between the amygdala and PFo. Given the importance of flexible, value-based decision making in cognition, we explored whether functional interactions with additional brain structures also make contributions to this type of behavior. Specifically, we assessed whether a part of the thalamus, called the magnocellular mediodorsal nucleus (MDm), or the nucleus accumbens (NA) works in concert with the PFo-amygdala circuit in guiding object choices in the reinforcer devaluation task. In this task, the value of rewards is varied by prior consumption of the food item that serves as a reward. Eating a certain kind of food leads to a selective satiation that decreases the value of that food. We chose to examine MDm, among the several thalamic nuclei, because neuroanatomical studies have shown that it is connected to PFo and relays information to PFo from brainstem and basal forebrain structures though to be important in emotion and motivation. We assessed the contribution of MDm and NA to reward-based choice behavior using a crossed-disconnection design. In this surgical preparation, subjects received selective lesions of the amygdala and PFo in one hemisphere and removal of either the NA or MDm in the other. This experimental procedure prevents intra-hemispheric interaction of both the amygdala and PFo with the brain region that has been removed in the other hemisphere (either NA or MDm). We then tested subjects on their ability to choose an object associated with food of a high value, compared to an object associated with food of a low (sated) value. We found that subjects with a disconnection of MDm from amygdala and PFo failed to adjust their object choices in the face of changes in the value of the goal. By contrast, subjects with a surgical disconnection of NA from amygdala and PFo had no such impairment. Thus, the MDm but not NA contributes to guiding flexible, reward-based decision making. This finding also shows that MDm must functionally interact with the amygdala and PFo to mediate this behavior (Izquierdo and Murray, 2010). Although subjects with combined unilateral lesions of amygdala and PFo were impaired on the reinforcer devaluation task immediately after surgery (Izquierdo et al., 2004), they did not differ from controls two years later, just before we carried out the crossed disconnection. Thus, unlike groups with bilaterally symmetrical lesions of PFo (Izquierdo et al., 2004) and the amygdala (Izquierdo and Murray, 2007), both of which exhibited impairments a year and a half following surgery, the group with unilateral amygdala plus PFo lesions within one hemisphere showed recovery of function. As just explained, research on this project has established that the amygdala plays an integral role in the ability of subjects to link objects with reward value. These findings show that the amygdala (and PFo) play a crucial role in stimulus valuation, especially when based on current (instantaneous) biological needs. It is also of interest to consider how subjects value actions. To investigate the role of the amygdala in goal-directed actions, we designed a new task. Subjects were trained to perform two different actions (tap and hold) on a touch-sensitive screen. Repetitive tapping of the screen produced one food;constant holding of the screen produced a different food. Subjects were given one of the foods, which lowered its value. This is the same selective satiation procedure explained above for the reinforcer devaluation task. As expected, controls showed a reduction in the action associated with a devalued food. In contrast, subjects with amygdala lesions failed to show this effect. This finding needs to be replicated, but if confirmed it provides strong support for the idea that the amygdala is as important for the valuation of actions as it is for the valuation of stimuli (and objects). In another major advance for this project, we have made progress in understanding the differential functions of two parts of PFo. Walkers areas 11 and 13 compose parts of what Price and his colleagues have identified as an orbital network of frontal areas. A medial network includes Walkers area 14. Thus, PFo, which comprises areas 11, 13 and 14, contributes to both networks. To explore the contribution of these subregions to emotional and goal-directed behavior, we studied subjects with restricted excitotoxic lesions of either areas 11 and 13 or area 14. Subjects with lesions restricted to areas 11 and 13 were significantly impaired on the devaluation task but not on an extinction task. In the extinction task, subjects learn to stop responding to a stimulus that they previously learned to be associated with a reward. Subjects with area 14 lesions exhibited the opposite pattern of results. Neither group differed from controls on object reversal learning or emotional responses, as assessed using the snake test. In the snake test, the latency to retrieve the food reward reflects subjects relative valuation of the object in contrast to the incentive value of the food. All three groups (area 11/13 lesions, area 14 lesions, and controls) behaved similarly in the snake test, readily retrieving the food in the presence of neutral objects, but taking longer to do so when presented with frightening objects. We also developed a new task to examine the transitivity of value judgments, which has been proposed as a PFo function. To test this idea, subjects were allowed to choose between objects that had been associated with different familiar foods, among which the subjects had an ordered preference. After the food associations had been learned, along with the differences between objects associated with them, subjects made choices between pairs of objects. If PFo is important for value-based transitivity, then subjects with PFo lesions should have difficulty in choosing objects based on their food preferences. We found that subjects with lesions of area 14, relative to controls, made more choices that were inconsistent with their overall preferences. Subjects with lesions of area 11/13 did not have this deficit. Previous work on this project revealed that the amygdala is not the only brain structure important for emotion. We found that selective hippocampal lesions, like amygdala lesions, led to blunted fear responses in the snake test, described above. In order to understand the independent contributions of the amygdala and hippocampus to fear expression, we compared amygdala and hippocampal function directly in this test. Subjects with selective excitotoxic lesions of either the amygdala or hippocampus both showed abnormally fast food-retrieval latencies in reaching over a frightening object. Both groups also exhibited fewer defensive behaviors and more approach behaviors when exposed to frightening objects. Thus damage to either structure blunted fear, but we found that it did so in different ways. Amygdala lesions led to an abnormal, excessive attention to the frightening objects, but hippocampal lesions led to behaviors that were unrelated to the objects (Chudasama et al. 2009). These data show that the hippocampus and amygdala contribute differently to defensive behavior. The hippocampus may boost arousal in threatening contexts or it might interact with the amygdala to prioritize behaviors, especially when consummatory and harm-avoidance behaviors conflict.